Process for preparing 2-[(N-2-pyridylcarbomyl)methyl]saccharin

ABSTRACT

Process for preparing 2-[(N-2-pyridylcarbomyl)methyl]saccharin of the formula ##STR1## using 1-methyl-2-chloropyridine-iodine as the condensing agent. The process involves reacting a mixture of 2-aminopyridine, tri-n-butylamine and 2-carboxymethyl saccharin (VIII), in dichloromethane, in the presence of 1-methyl-2-chloropyridine iodine (X).

This is a divisional of Ser. No. 631,616, filed July 17, 1984, now U.S.Pat. No. 4,587,335 granted on May 6, 1986, which is a divisional of Ser.No. 385,175, filed June 4, 1982, now U.S. Pat. No. 4,474,955 granted onOct. 2, 1984.

The present invention refers to a new process for preparing4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridinyl)carboxamide]-1,1-dioxideand its phosphoric ester, having respectively the following structuralformula: ##STR2## the compound (I), known under the generic name of"Piroxicam" is advantageously used therapeutically for itsanti-inflammatory activity.

The compound (II) according to the invention--that is the phosphoricester of compound (I)--is easily water-soluble, and can therefore beadvantageously injected.

According to the German patent application (publ. No 1 943 265) theproduct of formula (I) is obtained by reacting methyl3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-1,1-dioxide-3-carboxilate(III) with 2-aminopyridine (IV) by refluxing the xylenic solution. Thestarting product (III) is in turn obtained through stages will known inliterature.

Methyl 3-oxo-1,2-benzothiazine-1,1-dioxide-2-acetate (V) in dimethylsulfoxide with sodium methilate, by isomerization, gives3,4-dihydro-4-oxo-2H-1,2-benzothiazine-1,1-dioxide-3-methyl carboxylate(VI), which is methylated with methyl iodide and sodium hydrate inmethanol so that it produces the compound (III).

According to the above mentioned patent application, the synthesis isillustrated by the following scheme: ##STR3##

According to the U.S. Pat. No. 4,074,048, the compound (I) is obtainedby reacting4-hydroxy-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide(VII) in dimethylformamide, in the presence of sodium hydride, withmethyl iodide. The starting compound (VII) is obtained through thefollowing synthesis: 2-carboxymethyl saccharin (VIII) is reacted intetrahydrofuran in the presence of dicyclohexyl-carbodiimide orN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline with 2-aminopyridine (IV)to obtain 2-[(N-2-pyridylcarbamoyl)-methyl]saccharin (IX) which is inturn isomerized to obtain the compound (VII) in the presence of sodiummethylate in dimethylformamide or in dimethyl sulfoxide.

According to said U.S. patent, the synthesis is illustrated by thefollowing scheme: ##STR4##

According to the teachings of the German patent application No. 1 943265 the methylation of the intermediate (VI) gives a yield of about 55%,and the subsequent stage for the obtainment of (I) gives a yield ofabout 78%.

The total yield of the formation of the `Piroxicam` product, accordingto this route, is therefore of about 43% altogether. According to theU.S. Pat. No. 4,074,048, the formation of the intermediate (VIII) givesa yield of about 68%, and the methylation of the compound (VII) toobtain the product named `piroxicam` gives a yield of about 45%, thetotal yield being therefore of about 31%.

The main drawbacks of these methods, according to the prior art, consistin the very low yields, which become even lower if a quality product issought as, by means of the above mentioned methods, a rather impureproduct is achieved.

Many advantages are provided by the process according to the invention,allowing to obtain4-hydroxy-2-methyl-2H-1,2-benzothiazine-[N-(2-pyridyl)carboxamide]-1,1-dioxide(I) by applying the so-called `Phase-transfer Catalysis` to effect theN-methylation. Said process follows the teachings of E. V. Dehmlow,Angew. Chem. 86,187 (1974), Angew.Chem. Int.Ed.Engl. 13,170 (1974), andconsists in reacting4-hydroxy-2H-1,2-benzothiazine-3-[N-(2-pyridyl)carboxamide]-1,1-dioxide(VII) and its ester (XIII) with methyl iodide in the presence oftetrabutyl ammonium bromide, as a catalyst, and of potassium hydroxidein powder.

As a solvent, one may equally employ acetone, dimethylformamide,dimethyl sulfoxide, dimethylethane, acetonitrile and tetrahydrofuran;the two last solvents are those preferably used.

The invention relates also to the process for obtaining the phosphoricester of the compound (I). In particular, the syntheses according to theinvention are carried out as per the following schemes: ##STR5##

The `Phase-transfer Catalysis` is more advantageously employed than theknown N-alkylation methods, in that it gives higher yields in veryreduced times and at room temperature. In this specific case, due to thelow basicity of the heterocyclic nitrogen, the use of this method isindispensable if high yield (around 90%) and a first-rate product(minimum titre 99%) are sought. Furthermore, new and more advantageousmethods to produce the intermediates (VI) and (XIII) have been testedaccording to the invention, and namely: 2-carboxymethyl saccharin (VIII)is reacted in dichloromethane with 2-aminopyridine (VI) in the presenceof 1-methyl-2-chloropyridine iodine (X) and of tri-n-butylamine (XI);there is obtained 2-[(N-2-pyridylcarbomoyl)methyl]saccharin (IX) whichis isomerized by the usual techniques into4-hydroxy-2H-1,2-benzothiazine-3-[N-(2-pyridyl)carboxamide]-1,1-dioxide(III). The phosphoric ester of this derivative is obtained by reactingthe compound (VII) with phosphorous oxychloride in the presence ofPyridine.

The syntheses according to the invention are carried out as per thefollowing scheme: ##STR6##

Just by way of non-limiting example, reference is being made to someways of putting the invention into practice:

EXAMPLE 14-hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridyl)carboxamide]-1,1-dioxide(I)

A mix of 3.17 g (0.01 mols) of4-hydroxy-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide(VII), 1.42 g (0.01 mols) of methyl iodine, 0.325 g (0.001 mols) oftetrabutyl ammonium bromide, 0.62 g (0.011 mols) of potassium hydrate inpowder and 80 ml of tetrahydrofuran are energetically mixed at roomtemperature for one hour. The solvent is vacuum removed and the residuediluted with water. The pH is brought to 7.0 by means of HCl. Theinsoluble product is then filtered and crystallized from methanol and2.98 g of (I) (yield 98%, m.p. 195°-198° C.) are obtained.

EXAMPLE 24-phosphonooxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridyl)carboxamide]-1,1-dioxide(II)

A mix of 3.98 g (0.01 mols) of5-phosphonooxy-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide(XIII), 1.42 g (0.01 mols) of methyl iodine, 0.325 g (0.001 mols) oftetrabutyl ammonium bromide, 1.86 g (0.033 mols) of potassium hydrate inpowder and 40 ml of acetonitrile are energetically mixed at ambienttemperature for one hour. The insoluble product is filtered, ethanol isadded and the whole is neutralized. The sodium salt is filtered andacetone is added.

3.73 g of (II) (yield 90%; m.p. 245° C. with decomposition) precipitate.

EXAMPLE 3 2-[(N-2-pyridylcarbomoyl)methyl]saccharin (IX)

To 2.89 g (0.012 mols) of 1-methyl-2-chloropyridine iodine (X) there isadded a mix of 0.94 g (0.01 mols) of 2-aminopyridine (IV), 2.4 g (0.01mols) of 2-carboxymethyl saccharin (VIII) and 4.45 g (0.024 mols) oftri-n-butylamine in 100 ml dichloromethane. The mix is refluxed for onehour under nitrogen stream, 200 ml ether are added and the resultingmixture is washed three times with a 5% aqueous solution of hydrochloricacid. The organic layer is vacuum evaporated. The residue iscrystallized from methanol.

2.68 g of (IX) (yield 85%; m.p. 176°-178° C.) are obtained.

EXAMPLE 44-hydroxy-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide(VII)

To a solution of 1.6 g (0.005 mols) of (IX) warm dissolved in 5 mldimethyl sulfoxide there are added 0.80 g (0.015 mols) of sodiummethylate.

The whole is heated under stirring for 15' at 80°-90° C. The mixture ispoured in iced water and acidificated with acetic acid, and the yellowprecipitate (about 0.7 g of (VII) with m.p. 222°-224° C.) is filtered.

EXAMPLE 54-phosphonooxy-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide(XIII)

1.68 g (0.011 mols) of phosphorous oxychloride are dissolved in 10 mlpyridine at 20° C.

To the solution kept at 20° C. there are added under stirring in 5minutes' time 20 ml pyridine wherein 3.17 g (0.01 mols) of (VII) havebeen previously dissolved. The solution is kept at 20° C. for 10', thenthe temperature is slowly allowed to rise, in 10', to 0° C. There areadded under stirring 10 ml iced water and then a 10% solution of sodiumhydrate until the pH is 8.0.

The solution is extracted by means of chloroform.

The aqueous solution which separates is acidificated, treated withvegetal charcoal, filtered and vacuum dried. The residue is dissolved inabsolute alcohol. The compound (XIII) is filtered and precipitated withaddition of acetone.

4.3. g of product (m.p. 260°-261° C.) are obtained.

With regard to the phosphoric ester, clinical and pharmacological testshave been carried out, through which the following results have beenachieved:

the active ingredient of Piroxafos, namely the piroxicam phosphate, haslow acute toxicity when administered by the oral, subcutaneous andparenteral route to the mouse and rat; if administered subcutaneously tothe rat over a period of time much longer than that usually provided foraccording to clinical practice (45 days), Piroxafos is found to be welltolerated in doses corresponding to 8.3 DTD maximum (2.5 mg/Kg); indoses corresponding to 16.6 DTD max. (5 mg/Kg) the prolongued treatmentcauses a 25% death rate as well as a toxic symptomatology (such asdecrease in weight, anaemia, increase in azotemia and in SGPT andlesions of gastroenteric mucosa);

if administered subcutaneously to the dog in doses of 2 DTD max. over 45days consecutively, the drug is well tolerated and causes no toxiceffects;

if administered by the rectal route to the rabbit under the form ofsuppositories for 30 consecutively in doses corresponding to 10 DTDmax., the Piroxafos is well tolerated and without any general andtopical toxic effects;

if administered to the rat for 180 days consecutively, in oral doses 5and 10 times higher than the DTD max. (4 and 8 mg/Kg), the Piroxafosdoes not badly affect the biological and hematochemical parameters,though it may have irritating effects on the gastroenteric mucosa, andthis only if administered in the highest doses;

oral doses corresponding to 5 DTD max. administered to the dog over 180days consecutively are well tolerated and cause no toxic effects;

if administered to the rat 8 days before fecundation and until the 18thday of gestation in doses corresponding to 5 and 10 DTD max., thePiroxafos has no negative effect on the reproduction function, theadvancement of pregnancy and the embryofetal and neonatal development;

if administered to the rabbit from the 5th to the 17th day of gestation,in doses of 5 and 10 DTD max. by the oral route, and of 10 DTD max. bythe rectal route, the Piroxafos has no teratogenic effects;

the Piroxafos does not cause any alterations in the arterial pressure,breath and ECG basic values, after oral, subcutaneous andintraperitoneal treatment in doses 10 and 30 times higher than theaverage DTS adopted in the clinical field.

the ulcerogenic activity of Piroxafos, when administered in doses of 20mg/Kg corresponding to 50 average DTS, is decidedly lower than thatexerted by indomethacin ((10 mg/Kg);

after being tested on the rat and mouse according to differentexperimental methods, the Piroxafos proved to exert, in doses of 4 and 8mg/Kg, an antiinflammatory, analgetic and antipyretic activity.

I claim:
 1. A process for preparing2-[(N-2-pyridylcarbomoyl)methyl]saccharin (IX) comprising reacting amixture of 2-carboxymethyl saccharin (VIII), 2-aminopyridine (IV) andtri-n-butylamine, in dichloromethane, with 1-methyl-2-chloropyridineiodine (X); and recovering the resulting2-[(N-2-pyridylcarbomoyl)methyl]saccharin (IX).
 2. A process as in claim1 wherein 0.01 moles of 2-carboxymethyl saccharin (VIII), 0.01 moles of2-aminopyridine and 0.024 moles of tri-n-butylamine (XI), indichloromethane, are reacted with 0.01 moles of1-methyl-2-chloropyridine iodine (X).
 3. A process as in claim 2 whereinsaid reaction occurs in 100 mls of dichloromethane.
 4. A process as inclaim 3 further comprising refluxing the reaction mixture for about onehour under nitrogen steam.
 5. A process as in claim 4 wherein therecovery of 2-[(N-2-pyridylcarbomoyl)methyl]saccharin (IX) is effectedby adding ether to the reaction mixture, washing the resulting mixturethree times with a 5% aqueous solution of hydrochloric acid, vacuumevaporating the organic layer, and crystallizing the residue frommethanol.
 6. A process for preparing2-[N-2-pyridylcarbomoyl)methyl]saccharin (IX) comprising reacting amixture of 2-carboxymethyl saccharin (VIII), 2-aminopyridine (IV) andtri-n-butylamine in an organic solvent with 1-methyl-2-chloropyridineiodine (X) and recovering the resulting2-[(N-2-pyridylcarbomoyl)methyl]saccharin (IX).
 7. A process as in claim6 wherein 0.01 moles of 2-carboxymethyl saccharin (VIII), 0.01 moles of2-aminopyridine and 0.024 moles of tri-n-butylamine (XI) are reactedwith 0.01 moles of 1-methyl-2-chloropyridine iodine (X).